The human inherited disorders of sphingolipid metabolism (Gaucher, Krabbe, Farber, Niemann-Pick, etc.) are characterized by severe symptoms, particularly in their infantile forms, which exhibit severe mental retardation, neurological degeneration, and major organ involvement. Research on these disorders has been hampered by a lack of animals bearing the same genetic errors. We hope to induce model versions of these disorders by synthesizing and administering inhibitors of some sphingolipid hydrolases to young rats and mice. The ensuing progressive changes in brain and other organs will be followed by chemical assays, enzyme assays, isotope incorporation measurements, and morphological examination. Other compounds will be administered to rats and mice in an effort to slow the enzymes that synthesize the sphingolipids. It is possible that they will alleviate the symptom in the animals with the model disorders. Similarly, we will test compounds which stimulate the hydrolases to see if they can reverse the inhibition. Both classes of compounds will be tested with human tissues from patients with the genetic diorders to see if they are effective with the human enzymes. It is expected that the compounds will clarify the roles of the sphingolipids in normal and pathological brain function, as well as other functional roles. It is hoped that they will show low toxicity in animals and thereby exhibit potential in the alleviation of the symptoms of patients with sphingolipid genetic diseases.